Evidence-based treatment of a positive HPV DNA test Th. Agorastos Prof. of Obstetrics & Gynaecology Aristotle University Thessaloniki/GR
HPV DNA testing Indications 1. Triage after cytology with ASCUS/LSIL 2. Follow-up after surg. treatment (Laser Vap/LEEP/Cone) 3. Screening as co-testing or stand-alone test 4. Monitoring of vaccination efficacy
Distinction! HPV DNA testing HPV DNA genotyping (Combination!?)
Cumulative incidence of cervical intraepithelial neoplasia grade 3 and cancer ( CIN3) over a 10-year period in A) 7285 women younger than 30 years of age and B) 13 229 women 30 years old and older, according to oncogenic human papillomavirus (HPV) status at enrollment. (Khan M J et al. JNCI J Natl Cancer Inst 2005;97:1072-1079) The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org.
Prevalence of HPV in women with negative cytology by age (Wright et al, 2011) Prevalence of HPV hrhpv(14) HPV 16 HPV 18 --------------------------------------------------------------------------------------------------------------------------------------------------------- 30-39 years 9.0% 1.6% 0.7% 40-49 years 5.7% 0.7% 0.4% 50-59 years 5.3% 0.6% 0.4% 60-69 years 4.9% 0.7% 0.2% >=70 years 4.8% 0.8% 0.2% Overall 6.7% 1.0% 0.5%
HPV prevalence in screening population in Greece by age (Agorastos et al, 2009) Overall hrhpv prevalence: 5,79%
1. TRIAGE AFTER ABNORMAL CYTOLOGY
TRIAGE with HPV DNA test in cases with cytology as primary screening test HSIL+ No triage necessary! Colposcopy LSIL /mild dyscaryosis Risk of CIN2+ ~12% Very high proportion hrhpv DNA positive (55-80%)! HPV DNA testing useful? Genotyping? ASCUS/borderline alterations Risk of CIN2+ ~5% Low proportion hrhpv DNA positive (~14%) HPV DNA testing useful! Genotyping? Age!
Prevalence of hrhpv in women with LSIL by age (Cuzick et al, 2012) Prevalence of hrhpv ----------------------------------------------------------------------------------------------------------------------------------------- 21-24 years ~82% 25-29 years ~77% 30-34 years ~70% 35-39 years ~64% 40-44 years ~57% 45-49 years ~58% 50 and older ~54%
Prevalence of hrhpv in women with LSIL by age (Cuzick et al, 2012) NPP for CIN2+ for CIN3+ 21-29 y ~96% ~98% 30-39 y ~95% ~97% 40-49 y ~99% 100% 50 y and older 100% 100% PPV for CIN2+ for CIN3+ HPV16pos. ~25% ~14% HPV18 pos. ~10% ~8% 12 hrhpv pos. ~12% ~4%
HPV DNA testing in TRIAGE ASCUS/AGUS/LSIL/BMD in cytology HPV DNA testing negative positive Colpo 14hr types Follow-up other types (?) Genotyping/ (12- m) (Progr. markers)
2. FOLLOW-UP AFTER SURG. TREATMENT
2. HPV DNA testing in Follow-up after surgical treatment In comparison with follow-up cytology for predicting recurrence of CIN, HPV DNA testing is: more sensitive and equally specific (Arbyn et al, 2005, 2006) more sensitive but less specific (Heymans et al, 2011) more sensitive and equally specific (Kocken et al, 2012) NPV of a negative hrhpv test: 100%! (Heymans et al, 2011) HPV genotyping is the most sensitive and specific method to predict recurrent or persistent CIN 2-3 in the next 24 months (Heymans et al, 2011)
Follow-up after surgical treatment: HPV DNA testing more accurate than cytology!
HPV DNA testing in Follow-up after surgical treatment HPV DNA testing (+/- genotyping) negative positive Follow-up (12- m) Colposcopy (+/- Cytology)
3. SCREENING
3. HPV DNA testing in Screening HPV-based vs Cytology-based cervical screening Randomised trials have demonstrated for HPV-based screening: earlier detection of CIN3+ (Ronco, Rijkaart, Meijer) greater sensitivity (Cuzick, Bulkmans, Ronco, Naucler, Meijer, Dillner, Katki, Petry, Koliopoulos, Arbyn, ) double protection for double interval time (Cuzick) better protection from invasive cervical cancer (Sankaranarayanan, Ronco, Naucler, Rijkaart) better protection from advancer stages of cervical cancer (Sankaranarayanan) better protection from death from cervical cancer (Sankaranarayanan) However, HPV DNA testing is less (~6%) specific than cytology, especially in women aged <30 years, and lead to rel. high falsepositive results
Women <30 y with positive hrhpv DNA test Women with abnormal Pap test (>=LGSIL) ALL SCREENED WOMEN Women with high-grade lesion (CΙΝ2+)
Women >30 y with positive hrhpv DNA test Women with abnormal Pap test (>=LGSIL) ALL SCREENED WOMEN Women with high-grade lesion (CΙΝ2+)
ASC, ASCCP, ASCP screening guidelines, 2012
Cervical cancer risk for women undergoing Cumulative incidence rate for CIN3+ concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. Katki et al, Lancet Oncol, 2011 Juli according to baseline test results Dillner, J. et al. BMJ 2008 331,818 women, >30 y, 2003-2009 5-year incidence of CxCa HPV (-) & Pap (-) 3.2/100,000 HPV (-) 3.8/100,000 Pap (-) 7.5/100.000 Testing for HPV without adjunctive cytology might be sufficiently sensitive for primary screening for cervical cancer
Effect of Type-Specific Human Papillomavirus Incidence on Screening Performance and Cost (Agorastos et al, 2009)
Other HR incidence Other HR incidence Other HR incidence Cumulative missed CIN3+: 38% (model 1), 13% (model 2), 22% (model 3) 0.26 0.21 0-500 501-1000 1001-1500 1501-2000 2000-2500 2402 2402 2343 2461 Model 1 0.26 0-500 501-1000 Model 2 1001-1500 0.21 1501-2000 2000-2500 843 820 843 866 820 0.16 1758 1933 2051 2168 2226 2285 0.16 592 684 661 706 729 752 820 797 775 797 843 820 0.11 1172 1230 1406 1347 1289 1582 1523 1465 1640 1699 1875 1816 1992 2109 0.11 478 547 524 501 570 615 638 706 752 775 797 0.06 762 879 820 937 1055 996 1113 0.06 342 319 365 387 410 433 456 0.01 0.01 0.03 0.05 0.07 HPV16/18 incidence 0.26 0-500 501-1000 1001-1500 0.21 1501-2000 2000-2500 Model 3 0.01 0.01 0.03 0.05 0.07 1242 HPV16/18 incidence 1364 1333 1394 1364 1364 1424 0.16 1061 970 0.11 848 1000 1030 1121 0.06 545 606 576 636 758 667 697 727 788 818 939 1091 1152 1182 1212 1303 1273 909 879 0.01 0.01 0.03 0.05 0.07 HPV16/18 incidence
Primary screening for cervical cancer for different combinations of cytology, pooled hrhpv and HPV genotype 16/18 detection (The ATHENA HPV study, Cox et al, 2012) Conclusion: Primary screening with a pooled hrhpv test, that includes HPV 16/18 genotyping, appears to provide the best balance (sensitivity vs false positive results) among 9 different cervical screening strategies
Proposal for the MOST APPROPRIATE AND COST-EFFECTIVE METHOD FOR CERVICAL CANCER SCREENING One HPV DNA test every 5 years in all women aged 30-65 years C. Meijer (HPV test must be clinically validated! Meijer et al, IJC 2009)
HPV DNA testing in SCREENING HPV DNA testing negative positive Colpo 1y. 16/18 + Follow-up other hr + Genotyping (5y.)
Summary: Treatment of a positive hrhpv DNA test In case of existed ASCUS/LSIL Genotyping (+/- Progression markers) Colposcopy During post-treatment follow-up Colposcopy During regular primary screening Genotyping (+/- Progression markers) Colposcopy Cytology (?)
List of different HPV tests available in the market today
Validation and quality control of the HPV DNA tests Validated HPV tests: HC2, GP5+/6+, Cobas4800, Cervista
Future HPV tests: highly specific and sensitive!
4. MONITORING OF VACCINATION EFFICACY
4. HPV DNA testing as a method of monitoring of vaccination efficacy Prerequisites: Nationwide implementation of HPV-vaccination Introducing of HPV DNA testing as primary cervical cancer screening test Need for genotyping (at least 16/18) Screening in younger ages New technologies needed for monitoring of the second generation vaccines
Eυχαριστώ πολύ!